Rejected

In this study, we identified P14 alternate reading frame (P14ARF) as a novel regulator of inflammation and vascularization in intervertebral disc degeneration (IVDD). We collected IVD tissues from IVDD patients and normal individuals for analysis of P14ARF expression. We also induced experimental IVDD by needle puncture injuries in the caudal intervertebral discs of SD rats, and achieved recombinant adenovirus-mediated P14ARF overexpression in experimental IVDD rats. Regulation relationships between P14ARF and tissue inhibitors of metalloproteinases-3 (TIMP3) were confirmed in P14ARF-overexpressed and TIMP3-depleted nucleus pulposus (NP) cells. Tube formation was evaluated in coculture systems of human umbilical vein endothelial cells (HUVECs) and rat degenerated NP cells (DNPCs). Inflammatory response was assessed from levels of TNF-α, IL-1β and IL-6 and neovascularization from expression of endothelial growth factor (VEGF). The P14ARF and TIMP3 were downregulated in degenerated IVD tissue derived from patients and experimental IVDD rats. Over-expressed P14ARF suppressed inflammatory cytokines levels and vascularization. There was decreased tube formation in response to P14ARF overexpression and TIMP3 elevation. Finally, attenuated inflammatory responses and suppression of VEGF were achieved by P14ARF-mediated promotion of TIMP3 in rat DNPCs. Taken together, the present study reveals that P14ARF/TIMP3 modulation of inflammatory response and vascularization in the context of IVDD highlights a potential target for future therapeutic strategies.

We report the case of a 67-year-old woman who developed a cord of subcutaneous tissue extending from the axilla into the medial arm, accompanied by axillary neuropathic pain, with no history of surgery or infection. The patient was instructed in home exercises, and the condition progressively improved. Four months later, a small cord was visible on abduction with mild axillary dysesthesia, which was less severe than at onset. Diagnosis of exclusion was idiopathic axillary web syndrome (AWS). This syndrome is widely recognized after surgical axillary lymph node removal to treat breast cancer, but the etiopathogenesis is still unknown. Published reports of AWS with no history of surgery are rare, but a few reports have described this entity after infection or intense exercise. There are currently no previous reports of idiopathic AWS. The anatomical and clinical presentation, and clinical course of AWS without prior surgery, are similar to those of postoperative AWS.

Despite significant advances in treatment, chronic obstructive pulmonary disease (COPD) remains a chronic and progressive disease that frequently leads to premature mortality. COPD is associated with a constellation of significant symptoms including dyspnea, cough, wheezing, pain, fatigue, anxiety, depression and insomnia, and is associated with increased morbidity. Palliative care is appropriate to support these patients. However, historically palliative care has focused on supporting patients with malignant disease, rather than progressive chronic diseases such as COPD. Therapies for COPD often result in functional and symptomatic improvements including health-related quality of life (HRQL), and palliative care may further improve symptoms and health related quality of life (HRQL). Provision of usual palliative care therapies for this patient population requires understanding the pathogenesis of COPD and common, disease-targeted pharmacotherapies, as well as an approach to balancing life prolonging and HRQL care strategies. This review describes COPD and current targeted therapies and their effects on symptoms, exercise tolerance, HRQL, and survival. It is important to note that medications commonly used for symptom management in palliative care can interact with COPD medications resulting in increased risk of adverse effects, enhanced toxicity, or changes in clearance of medications. To address this, we review pharmacologic interactions with, and precautions related to use of COPD therapies in conjunction with commonly used palliative care medications.

On March 8, 2019, the FDA granted accelerated approval to atezolizumab in combination with paclitaxel protein-bound for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] of any intensity covering ≥ 1% of the tumor area), as determined by an FDA-approved test. Approval was based on data from IMpassion130, which randomized patients to receive atezolizumab or placebo in combination with paclitaxel-protein bound. Investigator-assessed progression-free survival (PFS) in the intent-to-treat (ITT) and PD-L1-positive populations were co-primary endpoints. After 13 months median follow-up, the estimated median PFS in the PD-L1-positive population was 7.4 months in the atezolizumab arm and 4.8 months in the placebo arm (HR 0.60, 95% CI 0.48-0.77). Overall survival results were immature with 43% deaths in the ITT population, representing 59% of the OS events required to perform the final OS analysis. Adverse reactions occurring in >20% of patients receiving atezolizumab with paclitaxel-protein bound were alopecia, peripheral neuropathies, fatigue, nausea, diarrhea, anemia, constipation, cough, headache, neutropenia, vomiting, and decreased appetite. Accelerated approval was appropriate taking into account the unmet medical need along with the immaturity of the OS results and potential for PFS in the PD-L1 expressing population to predict clinical benefit.

Delayed-onset muscle soreness (DOMS) is a common but displeasing event induced by excessive muscle use or unaccustomed exercise and characterized by tenderness and movement-related pain in the exercised muscle. Thermal therapy, either icing or heating applied to muscles immediately after exercise, has been used as therapeutic interventions for DOMS. However, the mechanisms of their analgesic effects, and physiological and metabolic changes in the muscle during thermal therapy remain unclear. In the present study, we investigated the effects of both thermal treatments on mechanical hyperalgesia of DOMS and physiological and muscle metabolite changes using the rat DOMS model induced by lengthening contraction (LC) to the gastrocnemius muscle. Heating treatment just after LC induced analgesic effects, while rats with icing treatment showed mechanical hyperalgesia similar to that of LC group. Furthermore, increased physiological responses (e.g., muscle temperature and blood flow) following the LC were significantly kept high only in the rats with heating treatment. In addition, heating treatment increased metabolites involved in the improvement of blood flow and oxidative metabolisms in the exercised muscle. The results indicated that heating treatment just after LC has analgesic effects on DOMS, which might be mediated partly through the improvement of muscle oxidative metabolisms by changes in metabolites and elevated physiological responses.

Artificial intelligence provides the opportunity to reveal important information buried in large amounts of complex data. Electronic health records (eHRs) are a source of such big data that provide a multitude of health related clinical information about patients. However, text data from eHRs, e.g., discharge summary notes, are challenging in their analysis because these notes are free-form texts and the writing formats and styles vary considerably between different records. For this reason, in this paper we study deep learning neural networks in combination with natural language processing to analyze text data from clinical discharge summaries. We provide a detail analysis of patient phenotyping, i.e., the automatic prediction of ten patient disorders, by investigating the influence of network architectures, sample sizes and information content of tokens. Importantly, for patients suffering from Chronic Pain, the disorder that is the most difficult one to classify, we find the largest performance gain for a combined word- and sentence-level input convolutional neural network (ws-CNN). As a general result, we find that the combination of data quality and data quantity of the text data is playing a crucial role for using more complex network architectures that improve significantly beyond a word-level input CNN model. From our investigations of learning curves and token selection mechanisms, we conclude that for such a transition one requires larger sample sizes because the amount of information per sample is quite small and only carried by few tokens and token categories. Interestingly, we found that the token frequency in the eHRs follow a Zipf law and we utilized this behavior to investigate the information content of tokens by defining a token selection mechanism. The latter addresses also issues of explainable AI.

Unfortunately, the author names in the author group section were incorrectly captured in the published online paper.

Multimodal pain management for surgery patients may include the use of a combination of scheduled oral pain medications with as-needed (PRN) oral opioids. Multiple concurrent time demands on nursing staff frequently cause delays in the delivery of oral PRN pain medication compromising pain management.

Currently, the role of transient receptor potential vanilloid type 4 (TRPV4), a nonselective cation channel in the pathology of spinal cord injury (SCI) is not recognized. Herein, we report the expression and contribution of TRPV4 in the pathology of scarring, endothelial and secondary damage after SCI. TRPV4 expression increased during the inflammatory phase in female rats after SCI and was expressed primarily by cells at endothelial-microglial junctions. Two-photon microscopy of intracellular free Ca levels revealed a biphasic increase at similar time points after SCI. Expression of TRPV4 at the injury epicenter, but not intracellular free Ca, progressively increases with the severity of the injury. Activation of TRPV4 with specific agonist altered the organization of endothelial cells, affected tight junctions in the hCMEC/D3 BBB cell line , and increases the scarring in rat spinal cord as well as induced endothelial damage. By contrast, suppression of TRPV4 with a specific antagonist or in female knockout mouse attenuated inflammatory cytokines and chemokines, prevented the degradation of tight junction proteins, and preserve blood-spinal cord barrier integrity thereby attenuate the scarring after SCI. Likewise, secondary damage was reduced, and behavioral outcomes were improved in knockout mice after SCI. These results suggest that increased TRPV4 expression disrupts endothelial cell organization during the early inflammatory phase of SCI, resulting in tissue damage, vascular destabilization, blood-spinal cord barrier breakdown, and scarring. Thus, TRPV4 inhibition/knockdown represents a promising therapeutic strategy to stabilize/protect endothelial cells, attenuate nociception and secondary damage, and reduce scarring after SCI.

The study compare two tests for evaluating the driving abilities of patients undergoing opioid therapy for chronic pain: the Vienna Test System (VTS), a software developed for this purpose, and a new free APP for smartphones (SafeDrive) measuring visual and auditory reaction times.